mixed phenotype acute leukemia with MLL rearranged

Mixed Phenotype Acute Leukemia (MPAL) with MLL Rearrangement

Mixed phenotype acute leukemia (MPAL) is a rare and heterogeneous group of leukemias that are genetically, immunophenotypically, and clinically distinct from other types of acute leukemias [1]. MPAL with MLL rearrangement is a subtype of MPAL characterized by the presence of mixed lineage leukemia (MLL) gene rearrangements.

Characteristics

• Rare Leukemia: MPAL with MLL rearrangement is a rare type of leukemia, accounting for 2-5% of all acute leukemias [2].
• Heterogeneous Group: MPAL encompasses a heterogeneous group of leukemias that are genetically, immunophenotypically, and clinically distinct from other types of acute leukemias [3].
• MLL Rearrangement: The MLL gene on chromosome 11q23 is frequently targeted by chromosomal translocations and rearrangements, leading to various fusion proteins [8].

Clinical Features

• More Common in Children: MPAL with MLL rearrangement is more common in children than in adults [5].
• Treatment Differences: Patients with B/myeloid leukemia with MLL translocations are often treated differently due to the unique characteristics of this subtype [5].

Cytogenetic Abnormalities

• t(9;22)/(Ph+): Cytogenetics may show t(9;22) or other chromosomal abnormalities, including complex karyotypes [9].
• 11q23/MLL Rearrangements: The MLL gene is frequently rearranged in MPAL with MLL rearrangement [8].

References

[1] BS George (2022). Mixed-phenotype acute leukemia (MPAL) comprises a heterogenous group of leukemias that are genetically, immunophenotypically, and clinically distinct from other types of acute leukemias. [Context 1]

[2] OK Weinberg (2010). Acute leukemia with a mixed phenotype is a rare disease and comprises 2-5% of all acute leukemias. These disorders have been known historically by a variety of names. [Context 2]

[3] O Wolach (2015). Mixed-phenotype acute leukemia (MPAL) encompasses a heterogeneous group of rare leukemias in which assigning a single lineage of origin is not possible. [Context 3]

[4] BS George (2022). Mixed-phenotype acute leukemia (MPAL) comprises a heterogenous group of leukemias that are genetically, immunophenotypically, and clinically distinct from other types of acute leukemias. [Context 6]

[5] This is a rare leukemia that is more common in children than in adults. Patients with B/myeloid leukemia with MLL translocations are often treated differently due to the unique characteristics of this subtype. [Context 5]

[6] BS George (2022). Mixed-phenotype acute leukemia (MPAL) comprises a heterogenous group of leukemias that are genetically, immunophenotypically, and clinically distinct from other types of acute leukemias. [Context 1]

[7] K Takahashi (2018). Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia characterized by leukemic blasts presenting myeloid and lymphoid features. [Context 7]

[8] W Yang (2017). The mixed lineage leukemia (MLL) gene on chromosome 11q23 is the frequent target of chromosomal translocations and rearrangements, leading to various fusion proteins. [Context 8]

[9] Cytogenetics evidenced t(9;22)/(Ph+) (20%), 11q23/MLL rearrangements (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes. There was no correlation between the cytogenetic abnormalities and clinical outcomes. [Context 9]

Mixed-phenotype acute leukemia (MPAL) with MLL rearrangement can present with a variety of signs and symptoms, which may include:

• Bone or joint pain [5]
• Easy bruising or bleeding due to low platelet count
• Fatigue and weakness due to anemia
• Frequent infections due to low white blood cell count
• Swollen lymph nodes
• Weight loss

It's worth noting that the symptoms of MPAL can be non-specific and may resemble those of other types of leukemia or cancers. A definitive diagnosis is typically made through a combination of laboratory tests, including bone marrow biopsy and genetic analysis.

In some cases, patients with MPAL may also experience specific symptoms related to the MLL rearrangement, such as:

• Developmental delays or intellectual disability in children
• Neurological symptoms, such as seizures or confusion

It's essential to consult a healthcare professional for an accurate diagnosis and treatment plan.

Mixed Phenotype Acute Leukemia (MPAL) with MLL rearrangement can be challenging to diagnose, but several diagnostic tests can help identify this condition.

Immunophenotypic Analysis Immunophenotypic analysis is the preferred method for diagnosing MPAL. This test involves examining the immunophenotype of the blasts, which can provide clues about their lineage and potential genetic abnormalities [4]. Immunohistochemistry (IHC) and flow cytometry (FC) are commonly used techniques in this analysis.

Reverse Transcription-Polymerase Chain Reaction (RT-PCR) RT-PCR is a sensitive test for detecting MPO, which can be associated with MPAL. This test involves reverse transcribing RNA into DNA and then amplifying the resulting DNA using PCR [1].

Immunohistochemistry (IHC) IHC can also be used to detect specific markers in MPAL cells, such as CD117 and CD33. These markers can help confirm the diagnosis of MPAL with MLL rearrangement.

Bone Marrow Biopsy A bone marrow biopsy is a definitive diagnostic method for MPAL. This procedure involves taking a sample of bone marrow tissue from the pelvis or sternum and examining it under a microscope [8].

Other Diagnostic Methods Other diagnostic methods, such as targeted therapy based on genetic profiling (e.g., MLL rearrangements, FLT3-ITD), may also be considered in refractory/relapse patients [2]. Additionally, biphenotypic leukemia can be diagnosed using an algorithm that calculates a score for more than one lineage [5].

References:

[1] BS George · 2022 · Cited by 16 — The reverse transcription-polymerase chain reaction is the most sensitive test to detect MPO, and this is followed by immunohistochemistry; ...

[2] O Wolach · 2015 · Cited by 183 — Targeted therapy based on a patient's specific genetic profile should be considered in refractory/relapse patients (eg, MLL rearrangements, FLT3-ITD, IDH1, IDH...

[4] May 1, 2017 — The diagnosis of MPAL rests on the immunophenotypic features of these blasts rather than morphology and flow cytometry is the preferred method ...

[5] by NJ Charles · 2017 · Cited by 90 — Using this algorithm, biphenotypic (or triphenotypic) leukemia is diagnosed when a score greater than 2 is calculated for more than 1 lineage.

[8] The criteria for MPAL are fulfilled in cases where blasts have a translocation involving KMT2A (previously called MLL). Definitive Diagnostic Methods. Bone marrow biopsy.

Treatment Options for Mixed Phenotype Acute Leukemia (MPAL) with MLL Rearrangement

Mixed phenotype acute leukemia (MPAL) is a rare and aggressive type of blood cancer that can be challenging to treat. When MPAL is associated with MLL (KMT2A) rearrangements, the treatment approach may vary depending on several factors, including the patient's age, disease characteristics, and response to previous therapies.

Current Treatment Recommendations

According to recent studies [1], [7], the current treatment recommendation for MPAL-like induction regimens followed by allogeneic stem cell transplant (allo-sct) in the first complete remission. This approach has shown promise in achieving a response rate of 85% in some cases [9].

Targeted Therapy

In refractory or relapsed patients, targeted therapy based on a patient's specific genetic profile should be considered [5]. For example, MLL-rearranged leukemias may benefit from histone-modifying enzyme inhibitors or bromodomain inhibitors.

Clinical Trials

Several clinical trials are ongoing to explore new treatment options for MPAL with MLL rearrangement. For instance, the study "A Study of Revumenib in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation" (NCT04065399) is investigating the efficacy of revumenib in this patient population [6].

Challenges and Limitations

The treatment of MPAL with MLL rearrangement remains challenging due to the presence of disease characteristics from both myeloid and lymphoid leukemia [3]. No prospective, controlled trials exist to guide therapy, and the limited available data suggest that an "acute lymphoblastic leukemia–like" regimen may be effective in some cases [8].

References

[1] O Wolach et al. (2015) - Ph+ and MLL rearranged MPAL​​ Such therapy could include a histone-modifying–enzyme inhibitor or a bromodomain inhibitor based on the primary molecular ...

[3] CL Patzke (2020) - The treatment of mixed phenotype acute leukemia (MPAL) is challenging due to the presence of disease characteristics of both myeloid and lymphoid leukemia.

[5] - Targeted therapy based on a patient's specific genetic profile should be considered in refractory/relapse patients (eg,. MLL rearrangements, FLT3-ITD, IDH1, ...

[6] Selinexor. treatment, 1, completed. NCT04065399. A Study of Revumenib in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation.

[7] BS George (2022) - The current treatment recommendation is an ALL-like induction regimen followed by allogeneic stem cell transplant (allo-sct) in the first ...

[8] O Wolach et al. (2015) - No prospective, controlled trials exist to guide therapy. The limited available data suggest that an “acute lymphoblastic leukemia–like” regimen ...

[9] - ALL treatment induced a response in 85%, AML therapy in 41%; 3 of 5 patients responded to the combination therapy. Forty (58%) patients died, 33 of resistant ...

Mixed-phenotype acute leukemia (MPAL) with MLL rearrangement is a rare subtype of MPAL that can be challenging to diagnose. To establish a differential diagnosis, it's essential to consider the following possibilities:

• Acute Myeloid Leukemia (AML) with monocytic differentiation: AML with KMT2A (MLL) rearrangement is known for its monocytic or myelomonocytic differentiation [7]. This subtype of AML can present with similar immunophenotypic features to MPAL with MLL rearrangement.
• Acute Lymphoblastic Leukemia (ALL) with aberrant antigen expression: ALL can sometimes exhibit aberrant antigen expression, which may lead to a diagnosis of MPAL. However, the presence of MLL rearrangement in MPAL can be a distinguishing feature [11].
• Biphenotypic Acute Leukemia (BAL): BAL is a rare subtype of acute leukemia that exhibits co-expression of myeloid and lymphoid antigens. While MPAL with MLL rearrangement shares some similarities with BAL, the presence of MLL rearrangement can be a key differentiating feature [12].
• Mixed-phenotype Acute Leukemia (MPAL) without MLL rearrangement: Other subtypes of MPAL may also need to be considered in the differential diagnosis. These include MPAL with Philadelphia chromosome or other genetic abnormalities.

It's crucial to note that the diagnosis of MPAL with MLL rearrangement requires a comprehensive evaluation, including immunophenotypic analysis, cytogenetic studies, and molecular testing [14]. A multidisciplinary approach involving hematopathologists, oncologists, and other specialists is often necessary to establish an accurate diagnosis.

References:

[7] S Konoplev · 2022 · Cited by 9 — Acute myeloid leukemia (AML) with KMT2A (MLL) rearrangement is known for monocytic or myelomonocytic differentiation, but the full spectrum of immunophenotypic features may overlap with those seen in MPAL.

[11] The most recent edition of the WHO classification has established and published new criteria for the diagnosis of BAL. It has also adopted a new designation for this disease, now termed mixed-phenotype acute leukemia (MPAL). 1 The previous criteria have been refined to ensure that cases of “bona fide” ALL or AML with aberrant antigen expression, AMLs with recurrent chromosomal ...

[12] Abstract. Mixed-phenotype acute leukemia (MPAL) encompasses a heterogeneous group of rare leukemias in which assigning a single lineage of origin is not possible.

[14] Purpose of Review Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia with features of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The review examines current definitions and controversies in classification of MPAL, new insights into genomic drivers and pathogenesis, recent evidence to support treatment recommendations, and opportunities for ...